Abstract In the United States, 60% of adults have a chronic disease and 40% have two or more. Collectively these diseases are the leading causes of death and disability accounting for >90% of our nation?s $3.3 trillion annual health care costs. Genome-wide association studies (GWAS) have identified genetic underpiinings of disease and enabled the development of polygenic risk scores (PRS) that may help to predict the occurrence and progression of common dieases. Working with the eMERGE team, we will select the fifteen diseases of public health impact. For these diseases, we will finalize the PRS to be adopted including adaptations (if any) for minority race groups, the genotyping array, the family history (FHx) tool and key clinical variables to be used in calculating genomic risk estimates (GRE). We will identify GRE thresholds at which genomic risk assessment (GRA) with risk reduction recommendations (RRR) in concordance with practice guidelines. To strengthen the evaluation of race-specific PRS, we bring an additional cohort of 30,0000 AAs. We will conduct a pilot ethical legal social implications study, to explore patient perspectives on use of FHx and PRS for estimating disease risk among Alabama Genomic Health Initiative (a state wide cohort) participants. The results will inform the development of consent, educational materials and a communication strategy to enhance recruitment and retention of eMERGE participants. We will prospectively recruit 2,500 patients with >75% patients from medically underserved communities, incorporate PRS, FHX and clinical data to compute GRE for the selected fifteen diseases for all patients. For high-risk patients, where GRE exceeds pre-specified thresholds (n~ 5000 of the 20,000 recruited across the network), deploy clinical decision support (CDS) and present the GRA and RRR. We expect ?50% uptake of RRRs. We will assess whether the uptake of GRA-RRR improve outcomes. We will assess three outcomes: uptake of GRA-RRR (implementation outcome), adherence to clinic visits (engagement outcome), and surrogates of disease / control (clinical outcome; e.g. blood sugar, cholesterol). Although research has identified genomic signatures of common diseases, genomic risk assessments to identify, and if appropriate, pre-treat at-risk patients have not been implemented in clinical care. This is the vital first step to leverage the power of genomics to prevent disease. We bring our expertise and experience to collaborate with the eMERGE investigative team to take this vital first step.